Preparation of methyl and ethyl n-



United States Patent PREPARATION OF METHYL AND ETHYL N-(S-NlTRO=2-THIAZOLYL) CARBAMATES Robert c. UNeiil, New York, N. Y., andArthur J. Basso, Railway, N. 3., assignors to Merck & Co., Inc.,Railway, N. 3., a corporation of New Jersey No Drawing. Application May14, 1956 Serial No. 584,462

2 Claims. (Cl. 260-3063) This invention relates to an improved processfor the preparation of alkyl N-(S-nitro-Z-thiazolyl) carbamates andnovel intermediates useful in said process. v V

The methyl and ethyl N-(5-nitro-2-thiazolyl) car bamates of the formula:

wherein R is a methyl or ethyl group, have been found to be valuabletherapeutic agents which are useful in the treatment of enterohepatitisin turkeys.

It is an object of the present invention to provide improved processesfor the preparation of alkyl N-(S-nitro- Z-thiazolyl) carbamates. novelintermediates useful in the synthesis of alkyl N-(S- nitro-2-thiazolyl)carbamates. Other objects will be apparent from the detailed descriptionof the invention hereinafter provided.

The improved process of the present invention, a two-step process,comprises reacting Z-aminothiazole with an alkyl haloformate to producethe corresponding alkyl N-(2-thiazolyl) carbamate and then nitrating thelatter compound to produce the desired alkyl N-(S-nitro- Z-thiazolyl)carbamate. These reactions can be shown structurally as follows:

Ej-NH, i Sj -NHEOB l olN- lj-Nni-on wherein R represents a methyl orethyl group and X represents chlorine or bromine.

The first step of the foregoing process is carried out by intimatelycontacting Z-aminothiazole with the alkyl halo formate, preferably inthe presence of a suitable inert solvent such as benzene, toluene,xylene, ethylene dichloride, dioxane, and the like. The formation of thedesired alkyl carbamate derivative is rapid and exothermic. Thus, thisfirst step of the process is conveniently effected by suspending theaminothiazole in the solvent, adding the alkyl haloformate and warmingthe reaction mixture on a steam bath. After completion of the reaction,the product which is precipitated can be conveniently separated from thesolvent. If desired, the product so obtained can be further purified bycrystallization from a suitable solvent such as ethanol.

Pursuant to a further embodiment of the present invention, it is foundthat the alkyl N-(Z-thiazolyl) carbamate can be conveniently nitrated byreaction with nitric acid in the presence of sulfuric acid to form theS-nitro derivative. Thus, the reaction is most conven- Another object isto provide n 2 iently effected by dissolving the alkyl H-(Zdhiazolyl)carbamate in concentrated sulfuric acid, and adding concentrated nitricacid -to the resulting cooled solution. In

carrying out this step of the process, it is found that maximum yieldsof the desired nitro derivative are obtained under optimum conditionswhen the reaction is carried out at a temperature within the range of-l0 to 10 C.

After completion of the nitration, the nitrated productv is convenientlyrecovered from the reaction mixture'by adding water to the reactionmixture and recovering the precipitated product by filtration.

The ethyl and methyl N-(5-nitr0-2-thiazo1yl) carbamates can also beprepared by the reaction of 2-amino-5- reaction conditions than does thepreparation of the carbamates of Z-amirio-S-nitrothiazole.

The following examples are presented as illustrative embodiments of thisinvention.

EXAMPLE 1 Preparation of ethyl N-(Z-thz'azolyl) carbamate 50 g. (0.5mol) of crude 2-aminothiazo1e was suspended in 200 ml. benzene. To thestirred slurry was added 24 ml. (0.25 mol) of ethyl chloroformate. Heatwas rapidly evolved, and a thick paste of the amine hydrochloridedeposited on the walls of the flask. The reaction mixture was heated onthe steam bath for one hour, and the clear supernatant was decanted.After evaporation of the benzene, the residual cream colored solid waswashedv well with Water, filtered and dried. The ethyl N-(2- thiazolyl)carbamate prepared in this way melted at.

l556 C. to a clear liquid. The carbamate crystallizes from aqueousethanol as colorless needles.

EXAMPLE 2 Preparation of methyl N-(Z-thiazolyl) carbamate Using theprocedure described in Example 1, methyl N-(Z-thiazolyl) carbamate, M.P. 172-1735 C., was prepared. This carbamate recrystallizes from aqueousmethanol or methanol as colorless matted needles.

The processes for the preparation of ethyl and methyl N-(Z-thiazolyl)carbamate shown in the foregoing examples can also be carried out in thesame manner using ethyl or methyl bromoformate in place of thechloroformate esters.

EXAMPLE 3 Preparation of ethyl N-(5-nitro-2-thiaz0lyl) carbamaze 5.16 g.(0.03 mol) of ethyl N-(2-thiazolyl) carbamate, prepared as describedabove, was dissolved in 15.5 ml. concentrated sulfuric acid at 0 C.While this solution was vigorously stirred at l0 to 0 C., 2.07 ml.(0.033 mol) of concentrated nitric acid was added dropwise. Afteraddition of the nitric acid, the clear yellow solution stood at 8 C. to0 C. for two hours, then was poured on ice. The nearly colorless productwhich deposited was filtered and washed Well with water. Additionalmaterial was obtained from the filtrate by adjusting the pH to 7 withsodium carbonate, and filtering the resulting precipitate. The ethylN-(5-nitro-2-thiazolyl) carbamate melted at 196-7 C.

. 3 EXAMPLE4 Preparation of methyl N-(S-rtitro-Z-thiazblyl) carbar na teThe mixed acid nitration procedure described in Example 3 Was employedto produce methyl N-(5-nitro-2- thiazolyl) carbamate. The-pr-oductprepared by this method was" of fine at 249 25 1 C.

quality, melting with decomposition The methyl or ethyl N-(5-nitro-2thiazolyl) carbamates are/very useful in treating turkeysinfected withblack head, and as prophylactics in preventing-the infection of turkeyflocks. These products are most convenientlyadministered orally bysuspending or dispersingthe carbam- 4 ate-compounds in the feed ordrinkingwater of the turkeys. The concentrationof the carbamatesin thefeed or; will depend upon-the; severity 'of the infection,

ageof the turkeys, etc. In general, it isfound-thata-con centration ofthe therapeutic agent of about 0.02% to about 0.2% in the feed or drinkis satisfactory. Amounts of the therapeutic agents within thisrangeshownotoxic eife'ctsand donot disturb the normallgrowth and-wellbeing-of the turkeys.

-The alkyl N-(5-nitro-2-thiazolyl) carbamates of the present'inventionare especially useful in treatingand:

preventing turkey blackhead infections since they form convenientlyadministered to turkey flocks in thedtinking water.'- i I 25 water"soluble alkali metal: salts and cantherefore' be Various changes andmodifications may be made in carryingoutthe presentinvention-withoutdeparting from the spirit and scope thereof. Insofar as these changesandmodifications are within the purview of the annexed claims, they are tobe considered as part of our invention.

What is claimed is: l. The process which comprisesintimately contactingnitric acid with.a solution of ethyl N-(Z-thiazolyl) carbamate inconcentrated sulfuric acid at a temperature within the range of about 10C. to 10 C. to produce ethyl N-(5-nitro-2-thiazolyl) carbamate.

2. The process'which comprises intimately. contacting nitric acid with.a solution of methyl N-(2-thiazolyl) carbamate in concentrated sulfuricacid at a temperature 2,531,756, 2,573,657: Steahly j Oct. 30, 1951OTHER REFERENCES l 2 Curry et al.: J. Am. Chem. Soc., vol. 73, pages5043-6 (1951).

WaletzyetalLs; Nov. 28, 1950

1. THE PROCESS WHICH COMPRISES INTIMATELY CONTACTING NITRIC ACID WITH ASOLUTION OF ETHYL N-(2-THIAZOLYL) CARBAMATE IN CONCENTRATED SULFURC ACIDAT A TEMPERATURE WITHIN THE RANGE OF ABOUT -10*C. TO 10*C. TO PRODUCEETHYL N-(5-NITRO-2-THIAZOLYL) CARBAMATE.